A common pharmacophore for cytotoxic natural products that stabilize microtubules Journal Article

   


Authors: Ojima, I.; Chakravarty, S.; Inoue, T.; Lin, S.; He, L.; Horwitz, S. B.; Kuduk, S. D.; Danishefsky, S. J.
Article Title: A common pharmacophore for cytotoxic natural products that stabilize microtubules
Abstract: Taxol (paclitaxel), a complex diterpene obtained from the Pacific yew, Taxus brevifolia, is arguably the most important new drug in cancer chemotherapy. The mechanism of cytotoxic action for paclitaxel - i.e., the stabilization of microtubules leading to mitotic arrest - is now shared by four recently identified natural products, eleutherobin, epothilones A and B, and discodermolide. Their ability to competitively inhibit [3H]paclitaxel binding to microtubules strongly suggests the existence of a common binding site. Recently, we have developed nonaromatic analogues of paclitaxel that maintain high cytotoxicity and tubulin binding (e.g., nonataxel). We now propose a common pharmacophore that unites paclitaxel, nonataxel, the epothilones, eleutherobin, and discodermolide, and rationalizes the extensive structure-activity relationship data pertinent to these compounds. Insights from the common pharmacophore have enabled the development of a hybrid construct with demonstrated cytotoxic and tubulin-binding activity.
Keywords: cancer chemotherapy; unclassified drug; paclitaxel; antineoplastic agents, phytogenic; cytotoxicity; structure activity relation; polymerization; magnetic resonance spectroscopy; models, molecular; molecular structure; pharmacophore; natural product; drug binding site; computer graphics; thiazoles; microtubule; alkaloids; microtubules; molecular conformation; drug binding; synthesis; molecular model; carbamates; epothilones; epothilone a; epothilone b; epoxy compounds; lactones; diterpenes; mitosis inhibition; discodermolide; eleutherobin; pyrones; priority journal; article; alkanes
Journal Title: Proceedings of the National Academy of Sciences of the United States of America
Volume: 96
Issue: 8
ISSN: 0027-8424
Publisher: National Academy of Sciences  
Date Published: 1999-04-01
Start Page: 4256
End Page: 4261
Language: English
DOI: 10.1073/pnas.96.8.4256
PUBMED: 10200249
PROVIDER: scopus
PMCID: PMC16319
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-0033551046&partnerID=40&md5=03731655277ba9f71e539f792c671ec9
Notes: Article -- Export Date: 16 August 2016 -- Source: Scopus
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MSK Authors
  1. Scott D Kuduk
    22 Kuduk
  2. Samuel J Danishefsky
    539 Danishefsky
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